Demonstration of calcitonin gene-related peptide immunoreactive axons contacting dynorphin A(1–8) immunoreactive spinal neurons in a rat model of peripheral inflammation and hyperalgesia

Injection of complete Freund's adjuvant (CFA; 75 μL) into the plantar surface of the hind paw of the rat results in a mild inflammation that lasts for several days and is accompanied by hyperalgesia. Multiple components of calcitonin gene related peptide (CGRP) neurotransmission in the spinal cord are altered during the course of this peripheral inflammation. The content of immunoreactive (i) CGRP in the dorsal horn of the spinal cord, where primary afferent neurons terminate, is significantly decreased within 2 days after injection of CFA but increases to a level greater than that of the control at 8 days. The early decrease in iCGRP in the spinal cord suggests that the release of CGRP from primary afferent neurons is increased during the period of maximal hyperalgesia that accompanies peripheral inflammation. Changes in the mRNA for CGRP suggest that the increase in spinal content of iCGRP is due to an increase in synthesis of the peptide as the level of mRNA for CGRP is increased from 2 to 8 days after injection of CFA. Despite the decrease in the content of iCGRP in the spinal cord, there is no apparent decrease in the amount of iCGRP that can be released from the dorsal spinal cord by capsaicin; in fact, capsaicin-evoked release is increased at 4 days. Measurements of the binding of 125I-labelled CGRP in the dorsal spinal cord indicate that high affinity binding sites for CGRP are downregulated at 4 days after injection of CFA. In total, these data support the hypothesis that the activity of CGRP-containing primary afferent neurons is increased during peripheral inflammation. CGRP released from primary afferent neurons in the spinal cord may contribute to cellular changes that accompany peripheral inflammation.Key words: calcitonin gene related peptide, dorsal root ganglion, hyperalgesia, inflammation, spinal cord.

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Increased calcitonin gene-related peptide in neuroma and invading macrophages is involved in the up-regulation of interleukin-6 and thermal hyperalgesia in a rat model of mononeuropathy

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2006.03856.x ◽

2006 ◽

Vol 98 (1) ◽

pp. 180-192 ◽

Cited By ~ 53

Author(s):

Weiya Ma ◽

Remi Quirion

Keyword(s):

Rat Model ◽

Interleukin 6 ◽

Thermal Hyperalgesia ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene

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Leukocyte Apheresis Using a Fiber Filter Suppresses Colonic Injury Through Calcitonin Gene–Related Peptide Induction

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz303 ◽

2019 ◽

Vol 26 (5) ◽

pp. 709-719

Author(s):

Hiroshi Yamasaki ◽

Keiichi Mitsuyama ◽

Shinichiro Yoshioka ◽

Kotaro Kuwaki ◽

Ryosuke Yamauchi ◽

...

Keyword(s):

Bone Marrow ◽

Blood Flow ◽

Disease Activity ◽

Inflammatory Cytokines ◽

Rat Model ◽

Tissue Expression ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene ◽

Colonic Blood Flow

Abstract Background The aim of this study was to address whether the therapeutic effect of leukocytapheresis (LCAP) depends on calcitonin gene– related peptide (CGRP) induction. Methods An HLA-B27 transgenic rat model was treated with an LCAP column. The effects of LCAP on clinical, endoscopic, and histologic disease activity, the colony-forming ability of colony-forming unit (CFU)–granulocyte macrophages (GMs), colonic blood flow, and tissue expression of tumor necrosis factor (TNF)–α and CGRP were examined. Changes in the effects of LCAP after pretreatment with the CGRP antagonist CGRP8–37 were also observed. A dextran sulfate sodium–induced colitis rat model included treatment with CGRP, and the effect was assessed based on clinical, endoscopic, and histologic disease activity, colonic blood flow, the colony-forming ability of CFU-GMs, and tissue expression of inflammatory cytokines and CGRP receptor families. Results LCAP improved disease activity, enhanced colonic blood flow, and induced the bone marrow colony-forming ability of CFU-GMs with an increase in CGRP mRNA levels. These effects were abolished by pretreatment with CGRP8–37. The administration of CGRP suppressed colitis, promoting colonic blood flow, inducing bone marrow–derived cells, downregulating inflammatory cytokines, and upregulating receptor activity–modifying protein–1. The mRNA and protein levels of inflammatory cytokines in lipopolysaccharide-stimulated mononuclear cells were also decreased after CGRP treatment. Conclusions The therapeutic effects of LCAP depend on CGRP induction. CGRP can effectively suppress colitis through the downregulation of inflammatory events and upregulation of protective events.

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Targeting CGRP via receptor antagonism and antibody neutralisation in two distinct rodent models of migraine-like pain

Cephalalgia ◽

10.1177/0333102419861726 ◽

2019 ◽

Vol 39 (14) ◽

pp. 1827-1837 ◽

Cited By ~ 10

Author(s):

Sarah L Christensen ◽

Steffen Petersen ◽

David Møbjerg Kristensen ◽

Jes Olesen ◽

Gordon Munro

Keyword(s):

Rat Model ◽

Time Course ◽

Calcitonin Gene Related Peptide ◽

Current Data ◽

Rodent Models ◽

Onset Of Action ◽

Related Peptide ◽

Pain Pathways ◽

Calcitonin Gene ◽

Cutaneous Hypersensitivity

Introduction Rodent disease models can play an indispensable role in drug development. Confirming that translationally-relevant disease mechanisms are engaged in such models is a crucial facet of this process. Accordingly, we have validated the role of calcitonin gene-related peptide signaling in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain by assessing their pharmacological responsiveness to the small molecule calcitonin gene-related peptide receptor antagonist olcegepant, and the humanised monoclonal calcitonin gene-related peptide antibody ALD405. Methods Cutaneous sensitivity to hind paw, and periorbital mechanical stimulation were used as surrogate markers of activation of relevant pain pathways in each respective model. Separate experiments were performed to identify the time-course of treatment response to olcegepant (1 mg/kg i.p.) and ALD405 (10 mg/kg i.p.). Results Olcegepant and ALD405 significantly alleviated cutaneous mechanical hypersensitivity in both models compared with corresponding control treatments (saline and IgG control antibody respectively). As expected, the duration of anti-nociceptive action obtained with ALD405 was considerably longer than that associated with olcegepant. Surprisingly, in the spontaneous rat model the onset of action of ALD405 occurred within just 4 hours after administration. Discussion The current data clearly show that calcitonin gene-related peptide-mediated signaling is critically involved in the manifestation of cutaneous hypersensitivity in distinct rodent models of migraine-like pain and emphasise their translational relevance. Moreover, the unexpected rapidity of onset observed for ALD405 supports i) a probable site of action outside the blood-brain barrier, and ii) a potential clinical utility of specific monoclonal calcitonin gene-related peptide antibodies in the abortive treatment of migraine.

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